Wiring diagram of the oxytocin system in the mouse brain

Abstract

Oxytocin (OT) neurons regulate diverse physiological responses via direct connections with different neural circuits. However, the lack of comprehensive input-output wiring diagrams of OT neurons and their quantitative relationship with OT receptor (OTR) expression presents challenges to understanding circuit specific OT functions. Here, we establish a whole-brain distribution and anatomical connectivity map of OT neurons, and their relationship with OTR expression using cell type specific viral tools and high-resolution 3D mapping methods. We utilize a flatmap to describe OT neuronal expression in four hypothalamic domains including under-characterized OT neurons in the tuberal nucleus. OT neurons in the paraventricular hypothalamus (PVH) broadly project to nine functional circuits that control cognition, brain state, and somatic visceral response. In contrast, OT neurons in the supraoptic (SO) and accessory nuclei have limited central projection to a small subset of the nine circuits. Surprisingly, quantitative comparison between OT output and OTR expression showed no significant correlation across the whole brain, suggesting abundant indirect OT signaling in OTR expressing areas. Unlike output, OT neurons in both the PVH and SO receive similar mono-synaptic inputs from a subset of the nine circuits mainly in the thalamic, hypothalamic, and cerebral nuclei areas. Our results suggest that PVH-OT neurons serve as a central modulator to integrate external and internal information via largely reciprocal connection with the nine circuits while the SO-OT neurons act mainly as unidirectional OT hormonal output. In summary, our OT wiring diagram provides anatomical insights about distinct behavioral functions of OT signaling in the brain. Significance StatementOxytocin (OT) neurons regulate diverse physiological functions from pro-social behavior to pain sensation via central projection in the brain. Thus, understanding detailed anatomical connectivity of OT neurons can provide insight on circuit specific roles of OT signaling in regulating different physiological functions. Here, we utilize high resolution mapping methods to describe the 3D distribution, mono-synaptic input and long-range output of OT neurons, and their relationship with OT receptor (OTR) expression across the entire mouse brain. We found OT connections with nine functional circuits controlling cognition, brain state, and somatic visceral response. Furthermore, we identified a quantitatively unmatched OT-OTR relationship, suggesting broad indirect OT signaling. Together, our comprehensive OT wiring diagram advances our understanding of circuit specific roles of OT neurons.